Abstract
An injection of orexin A or B into the cisterna magna or the rostral ventrolateral medulla (RVLM), where bulbospinal vasomotor neurons are located, elevated arterial pressure (AP) and heart rate (HR). We examined how orexins affected RVLM neurons to regulate cardiovascular functions by using in vitro recordings of neuronal activity of the RVLM and in vivo measurement of cardiovascular functions in rats. Orexin A and B concentration-dependently depolarized RVLM neurons. At 100 nM, both peptides excited 42% of RVLM neurons. Tetrodotoxin failed to block orexin-induced depolarization. In the presence of N-(2-methyl-6-benzoxazolyl)-N′-1, 5-naphthyridin-4-yl urea (SB-334867), an orexin 1 receptor (OX1R) antagonist, orexin A depolarized 42% of RVLM neurons with a smaller, but not significantly different, amplitude (4.9 ± 0.8 versus 7.2 ± 1.1 mV). In the presence of (2S)-1- (3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride (TCS OX2 29), an orexin 2 receptor (OX2R) antagonist, orexin A depolarized 25% of RVLM neurons with a significantly smaller amplitude (1.7 ± 0.5 mV). Coapplication of both antagonists completely eliminated orexin A-induced depolarization. An OX2R agonist, [Ala11,d-Leu15]-orexin B, concentration-dependently depolarized RVLM neurons. Regarding neuronal phenotypes, orexins depolarized 88% of adrenergic, 43% of nonadrenergic, and 36 to 41% of rhythmically firing RVLM neurons. Intracisternal TCS OX2 29 (3 and 10 nmol) suppressed intracisternal orexin A-induced increases of AP and HR, whereas intracisternal SB-334867 (3 and 10 nmol) had no effect on the orexin A-induced increase of HR but suppressed the orexin A-induced pressor response at 10 nmol. We concluded that orexins directly excite RVLM neurons, which include bulbospinal vasomotor neurons, and regulate cardiovascular function mainly via the OX2R, with a smaller contribution from the OX1R.
Footnotes
This work was supported by the National Health Research Institutes of Taiwan [Grants NHRI-EX97-9605NI, NHRI-EX98-9605NI].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167791.
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ABBREVIATIONS:
- RVLM
- rostral ventrolateral medulla
- AP
- arterial pressure
- CNQX
- 6-cyano-7-nitroquinoxalene-2,3-dione
- AP-5
- 2-amino-5-phosphopentanoic acid
- DMSO
- dimethyl sulfoxide
- HR
- heart rate
- MAP
- mean arterial pressure
- OX1R
- orexin 1 receptor
- OX2R
- orexin 2 receptor
- PNMT
- phenylethanolamine N-methyltransferase
- SB-334867
- N-(2-methyl-6-benzoxazolyl)-N′-1,5-naphthyridin-4-yl urea
- TCS OX2 29
- (2S)-1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-[(4-pyridinylmethyl)amino]-1-butanone hydrochloride
- TTX
- tetrodotoxin
- ANOVA
- analysis of variance
- PBS
- phosphate-buffered saline
- SD
- Sprague-Dawley
- ALOXB
- [Ala11d-Leu15]-orexin B.
- Received March 4, 2010.
- Accepted May 20, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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